American trypanosomiasis or Chagas disease, caused by the protozoan Trypanosoma cruzi, is a vector-borne neglected tropical disease. The causative parasite is endemic in 21 Latin American countries and as of now infects about 6 to 7 million people in that geographic region and imposes a large economic burden on people of these countries with widespread poverty. The parasite also imposes a global threat because of population migration, which brings it to the USA, Canada, Europe, and Western Pacific countries. Unfortunately, the effectiveness of available therapeutics for the Chagas disease is limited by long-term therapy, serious side effects, and inadequacy in the chronic phase of the disease, thus demands development of new therapeutic agents. Recently, an N-methylated peptide, naranjamide, was discovered by bioactivity-guided fractionation from a Panamanian cyanobacterium, which showed an inhibition of 81.51% of T. cruzi. The structure of the compound was elucidated by using NMR and MS/MS. We completed the total synthesis of naranjamide with commercially available building blocks. The reaction scheme utilized four types of reactions including peptide coupling, ester hydrolysis, Boc-deprotection, and N-methylation of amides. The major peptide coupling reaction employed was N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) coupling with 1-hydroxybenzotriazole (HOBt) as an additive. HATU mediated coupling reaction was also performed in the final step of the synthesis. Base (NaH) promoted methylation with methyl iodide (MeI) yielded the N-methyl version of the corresponding amide. To obtain a better insight of the structure-activity relationship of the lead compound, several series of naranjamide analogs have been designed. Here we also report the synthesis of a series of naranjamide analogs that constitutes both methylated and non-methylated peptides with variation in their chain length, and positions of amino acids. Analogs synthesis applied the similar set of reactions used for naranjamide synthesis. The anti-parasitic activity of these analogs will be presented. Other analogs, designed with modification in the head and tail part of the peptide, will be reported in future.

Panamanian cyanobacterial metabolite with antitrypanosomal activity

254th National Meeting (2017)

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